1. Field of the Invention
This invention relates to a method of treating multiple myeloma using 17-allylamino-17-demethoxygeldanamycin or 17-aminogeldanamycin, or a prodrug of either.
2. Description of Related Art
Multiple myeloma (“MM”, also known as myeloma or plasma cell myeloma) is an incurable but treatable cancer of the plasma cell. Plasma cells are an important part of the immune system, producing immunoglobulins (antibodies) that help fight infection and disease. MM is characterized by excessive numbers of abnormal plasma cells in the bone marrow (“BM”) and overproduction of intact monoclonal immunoglobulins (IgG, IgA, IgD, or IgE; “M-proteins”) or Bence-Jones protein (free monoclonal light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of MM. MM is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.
Therapies for MM include chemotherapy, stem cell transplantation, high-dose chemotherapy with stem cell transplantation, and salvage therapy. Chemotherapies include treatment with Thalomid® (thalidomide), Velcade® (Bortezomib), Aredia® (pamidronate), steroids, and Zometa® (zoledronic acid). However many chemotherapy drugs are toxic to actively dividing non-cancerous cells, such as cells of the BM, the lining of the stomach and intestines, and the hair follicles. Therefore, chemotherapy may result in a decrease in blood cell counts, nausea, vomiting, diarrhea, and loss of hair.
Conventional chemotherapy, or standard-dose chemotherapy, is typically the primary or initial treatment for patients with MM. Patients also may receive receive chemotherapy in preparation for high-dose chemotherapy and stem cell transplant. Induction therapy (conventional chemotherapy prior to a stem cell transplant) can be used to reduce the tumor burden prior to transplant. Certain chemotherapy drugs are more suitable for induction therapy than others, because they are less toxic to BM cells and result in a greater yield of stem cells from the BM. Examples of chemotherapy drugs suitable for induction therapy include dexamethasone, thalidomide/dexamethasone, VAD (vincristine, Adriamycin® (doxorubicin), and dexamethasone in combination), and DVd (pegylated liposomal doxorubicin (Doxil®, Caelyx®), vincristine, and reduced schedule dexamethasone in combination).
The standard treatment for MM is melphalan in combination with prednisone (a corticosteroid drug), achieving a response rate of 50%. Unfortunately, melphalan is an alkylating agent and is less suitable for induction therapy. Corticosteroids (especially dexa-methasome) are sometimes used alone as MM therapy, especially in older patients and those who cannot tolerate chemotherapy. Dexamethasone is also used as a form of induction therapy, alone or in combination with other agents. VAD is the most commonly used induction therapy, but DVd has recently been shown to be effective as induction therapy. Bortezomib has been approved recently for the treatment of MM, but it is very toxic. However, none of the existing therapies offer a significant potential for a cure.
17-Allylamino-17-demethoxygeldanamycin (“17-AAG”, also sometimes referred to as 17-allylaminogeldanamycin) is a semi-synthetic analog of the naturally occurring compound geldanamycin (Sasaki et al., 1981). Geldanamycin is obtainable by culturing a producing organism, such as Streptomyces hygroscopicus var. geldanus NRRL 3602. Another biologically active geldanamycin derivative is 17-aminogeldanamycin (“17-AG”), which is produced in the human body by metabolism of 17-AAG. 17-AG can also be made from geldanamycin (Sasaki et al. 1979). While geldanamycin and its analogs have been studied intensively as anti-cancer agents in the 1990s (e.g., Sasaki et al., 1981; Schnur, 1995; Schnur et al., 1999), none of them has been approved for anti-cancer use.

17-AAG and geldanamycin are believed to act by binding to and inhibiting the activity of heat shock protein-90 (“Hsp90”) (Schulte and Neckers, 1998). Hsp90 acts as a chaperone for the normal processing of many cellular proteins (“client proteins”) and is found in all mammalian cells. Stress (hypoxia, heat, etc.) induces a several-fold increase in its expression. There exist other stress induced proteins, such as heat shock protein-70 (“Hsp70”), which also play a role in cellular response to and recovery from stress.
In cancer cells, Hsp90 inhibition leads to disruption of the interaction between Hsp90 and its client proteins, such as erbB2, steroid receptors, raf-1, cdk4, and Akt. For example, exposure to 17-AAG results in depletion of erbB2 and destabilization of Raf-1 and mutant p53 in SKBr3 breast cancer cells (Schulte and Neckers, 1998), depletion of steroid receptors in breast cancer cells (Bagatell et al., 2001), depletion of Hsp90 and down-regulation of Raf-1 and erbB2 in MEXF 276 L melanoma cells (Burger et al., 2004), depletion of Raf-1, c-Akt, and Erk1/2 in colon adenocarcinoma cells (Hostein et al., 2001), down-regulation of intracellular Bcr-Ab1 and c-Raf proteins and reduction of Akt kinase activity in leukemia cells (Nimmanapalli et al., 2001), degradation of cdk4, cdk6, and cyclin E in lung cancer cells with wild-type Rb (Jiang and Shapiro, 2002), and depletion of erbB 1 (EGFR) and erbB2 (p185) levels in NSCLC cells (Nguyen et al., 2000).
Because of the activity of 17-AAG relative to Hsp90 and other proteins involved in oncogenesis and metastasis of cancer cells, a number of clinical investigators have evaluated its effectiveness as an anti-cancer agent in human clinical trials. From these various trials, the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute recommended these Phase 2 dose/schedule regimens for further study: 220 mg/m2 (mg per square meter of body surface area of the patient or subject) administered twice weekly for 2 out of 3 weeks, 450 mg/m2 administered once a week continuously or with a rest or break, and 300 mg/m2 once a week for 3 weeks out of 4 weeks. Results of various clinical trials—almost exclusively with patients having solid tumors—with 17-AAG generally showed limited clinical activity and are summarized below:    (a) A Phase 1 trial in adult patients with solid tumors was conducted in which patients received 17-AAG daily for 5 days every 3 weeks. The starting dose was 10 mg/m2 and was escalated to 56 mg/m2, with a maximum tolerated dose (“MTD”) and recommended Phase 2 dose defined as 40 mg/m2. The protocol was amended to exclude patients with significant pre-existing liver disease, after which patients were treated at doses up to 110 mg/m2 on the same schedule. No objective tumor responses were observed. Due to dose limiting reversible hepatotoxicity, the protocol was further amended to dose patients on a twice weekly schedule every other week starting at a dose of 40 mg/m2 per day. At daily doses of 40 and 56 mg/m2 for 5 days, the peak plasma concentrations were 1,860±660 and 3,170±1,310 nM, respectively. For patients treated at 56 mg/m2 average AUC values for 17-AAG and 17-AG were 6,708 and 5,558 nM*h, respectively, and average t1/2 3.8 and 8.6 hours, respectively. Clearances of 17-AAG and 17-AG were 19.9 and 30.8 L/h/m2, respectively, and Vz values were 93 and 203 L/m2, respectively (Grem et al., 2005).    (b) In a second Phase 1 trial, patients with advanced solid tumors received 17-AAG on a daily×5 schedule at a starting dose of 5 mg/m2. At the 80 mg/m2, dose limiting toxicities (hepatitis, abdominal pain, nausea, dyspnea) were observed but dose escalations nevertheless were continued until the dose reached 157 mg/m2/day. Further dose schedule modifications were implemented to allow twice weekly dosing. At the 80 mg/m2 dose level, the t1/2 was 1.5 hours and the plasma Cmax was 2,700 nM. Similarly, for 17-AG the t1/2 was 1.75 hours and the Cmax was 607 nM. Plasma concentrations exceeded those needed to achieve cell kill (10-500 nM) in in vitro and in vivo xenograft models (Munster et al., 2001).    (c) A Phase 1 trial of 17-AAG was conducted in which patients with advanced solid tumors were treated weekly for 3 out of every 4 weeks at a starting dose of 10 mg/m2, with a recommended Phase 2 dose of 295 mg/m2. Dose escalations reached a dose of 395 mg/m2, at which nausea and vomiting secondary to pancreatitis and grade 3 fatigue were observed. The dosing schedule was amended to allow dosing twice weekly for 3 out of every 4 weeks and twice weekly for 2 out of every 3 weeks. A population pharmacokinetic (PK) analysis was performed on data obtained from this trial. The Vd (volume of distribution) for 17-AAG was 24.2 L for the central compartment and 89.6 L for the peripheral compartment. Clearance values were 26.7 L/h and 21.3 L/h for 17-AAG and 17-AG, respectively. Metabolic clearance indicated that 46.4% of 17-AAG was metabolized to 17-AG. No objective tumor responses have been observed in this trial to date. (Chen et al., 2005).    (d) Another Phase 1 trial in patients with solid tumors and lymphomas was conducted using a weekly dosing for 3 weeks out of a 4 week cycle. The starting dose was 15 mg/m2. Dose escalation reached 112 mg/m2 without significant toxicity and were continued with an objective of reaching a dose range of “biological” activity. The MTD for weekly 17-AAG was reached at 308 mg/m2. No objective tumor responses have been observed to date in this trial, and the levels of Hsp90 client proteins measured were unchanged during therapy. No correlation between chaperone or client protein levels and 17-AAG or 17-AG PK was seen. There was also no correlation between the 17-AAG PK and its clinical toxicity (Goetz et al., 2005).    (e) Another Phase 1 trial was conducted using a once weekly administration schedule, including 11 patients with metastatic melanoma. The starting dose was 10 mg/m2, and dose limiting toxicity was observed at 450 mg/m2/week (grade ¾ elevation of AST). At higher doses (16-450 mg/m2/week) the 17-AAG formulation employed contained 10-40 mL dimethylsulfoxide (DMSO) in a single infusion, which likely contributed to the gastrointestinal toxicity that was observed in the trial. Among the patients treated at 320-450 mg/m2, two showed radiologically documented long term stable disease. No complete or partial responses were recorded. At the highest dose level (450 mg/m2) the plasma 17-AAG concentrations exceeded 10 μM and remained above 120 nM for periods in excess of 24 hours. At the highest dose level of 450 mg/m2, the mean volume of distribution was 142.6 L, mean clearance was 32.2 L/h, and the mean peak plasma level was 8,998 μg/L. There was a linear correlation between dose and area under the curve (AUC) for the dose levels studied. Pharmacodynamic (PD) parameters were also measured and induction of the co-chaperone protein Hsp70 was observed in 8 of 9 patients treated at 320-450 mg/m2/week. Depletion of client proteins was also observed in tumor biopsies: CDK4 in 8 out of 9 patients and Raf-1 depletion in 4 out of 6 patients at 24 hours. These data indicated that Hsp90 in tumors is inhibited for between 1 and 5 days. (Banerji et al., 2005).
The in vivo anti-MM activity of 17-AAG has been studied using a model of diffuse GFP positive MM lesions in SCID/NOD mice (Mitsiades et al., 2006). Survival analysis showed that treatment significantly prolonged median overall survival, but non-clinical data are frequently not predictive of clinical activity. As discussed above, this has particularly been the case for 17-AAG in solid tumors, where the promise of pre-clinical data has not been borne out in Phase 1 clinical trials.
Thus, despite intensive efforts to develop 17-AAG as an anti-cancer agent, no regulatory agency has approved it for the treatment of any cancer. There remains a need for methods of dosing and administering 17-AAG and prodrugs of 17-AAG (and its metabolic counterpart 17-AG) so that its potential therapeutic benefits can be realized. The present invention provides such methods that are efficacious in the treatment of MM using 17-AAG.
A list references cited herein is provided at the end of this specification. All documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually incorporated herein by reference.